1. Field of the Invention
This invention relates to the prophylactic and therapeutic treatment of disorders using targeted delivery of therapeutic agents, and more particularly to the prophylactic and therapeutic treatment of disorders associated with the eye or nasal tissues.
2. Description of the Background Art
Drug delivery takes a variety of forms, depending on the agent to be delivered and the administration route. The most convenient way to administer drugs in the body is by oral administration, however many drugs, in particular proteins and peptides, are poorly absorbed and unstable during passage through the GI tract. Further, oral delivery is ineffective for treating many disorders of the eye, the brain, and other tissues, due to the presence of barriers such as the blood-retinal barrier, and the blood-brain barrier, which limit the passage of most agents. Oral delivery also results in high systemic levels, thus potentially leading to systemic side effects.
Targeted drug delivery means are increasingly desirable, because they minimize toxic side effects, lower the required dosage amounts, localize drug release and delivery, and decrease costs for the patient. Targeted drug delivery is particularly advantageous for administration methods that are not particularly effective, or that result in poor bioavailability, for example topical administration to the mucosal, ocular, or nasal tissues. In particular, targeted drug delivery provides a non-invasive method of delivering drugs to a tissue to be treated, as well as enabling patients to self-administer medication. Targeted drug delivery also enables the potential of remotely administering medicine, for example nasally administering a targeted compound to treat a disorder of the reproductive system or remote cancers.
Topical treatment of ophthalmic disorders is preferred in many cases because a topical composition may be self-administered by a patient, and does not require the co-administration of anesthetics. Topical compositions are generally ineffective at delivering a therapeutically effective amount of an active ingredient to the anterior and posterior segments of the eye, however, due to short residence time and inadequate penetration. For example, the secretion and drainage of the lacrimal fluid bring about a rapid elimination of conventional dosage forms administered to the eye. For example, only about 50% of an instilled drop remains about 1 minute after administration, and the remainder is rapidly cleared within the next 5 minutes. Due to this brief contact time, only a small fraction of a drug is able to enter the eye tissue, and then cross through the conjunctiva, cornea, and sclera to reach intraocular tissues. Moreover, even if a drug is able to penetrate through some layers of tissue, many drugs do not possess requisite penetration ability with regard to some other tissues of the eye such that an effective dose can be imparted.
The nasal administration route has emerged in recent years as convenient for the delivery of drugs, particularly peptide and protein drugs that have poor oral availability, for example, calcitonin, buserelin, and nafarelin. Because the nasal route is non-invasive and makes self-medication practical, it improves patient compliance when compared with the parenteral route. However, proteins and peptide intra-nasal delivery is considerably less effective than the parenteral route, and the bioavailability is often less than 5%. This poor bioavailability is due in part to pre-systemic elimination due to enzymatic degradation and poor mucosal membrane permeability. Further, some medications administered in the olfactory region are able to access parts of the brain without entering the blood stream, and thus nasal administration can be a direct pathway for brain delivery of drugs. However, the efficiency and the extent of drug absorption using conventional nasal to brain delivery means is low.
Pulmonary delivery is desirable for delivery of protein and peptide drugs, because the large absorptive surface area of the lungs (140 m2 vs 180 cm2 for the nasal route) promotes high absorption. For example, the bioavailability of leuprolide is 2.9% when administered as a nasal solution, but 28% when administered as a suspension aerosol. However, there are several barriers in the lungs that must be overcome before a drug can reach systemic circulation. First, the bioavailability is limited by the maximum deposition of drugs in the alveolar region with the existing devices, which is about 30%. In addition, degradation of peptides in the lungs by alveolar macrophages, epithelial cells, and secreted proteolytic enzymes in the alveolar fluids limit peptide delivery via the lungs. Poor membrane permeability is also a major barrier. These problems have not been overcome by particulate delivery systems, which tend to make engulfment by macrophages (and expulsion from the lungs) more efficient.
What is needed is an improved delivery vehicle for targeting therapeutic agents that overcomes these tissue permeability difficulties, and results in increased uptake and transport of drugs across tissue, particularly mucosal tissues including ocular and nasal tissues. Also needed are methods of targeting the delivery of a therapeutically effective amount of a therapeutic agent, for prophylactic, therapeutic, and diagnostic purposes.